Vaccine-induced cellular immunity controls virus replication in simian immunodeficiency virus (SIV)-infected monkeys only transiently, leading to the question of whether such vaccines for AIDS will be effective. We immunized monkeys with plasmid DNA followed by replication defective adenoviral vectors encoding SIV proteins and challenged them with pathogenic SIV. Although these monkeys demonstrated a reduction in viremia restricted to the early phase of SIV infection, they showed a prolonged survival. This survival was associated with preserved central memory CD4+ T lymphocytes and could be predicted by the magnitude of the vaccine-induced cellular immune response. These immune correlates of vaccine efficacy should guide the evaluation of AIDS vaccines in humans.[unreadable] [unreadable] [unreadable] These findings suggest that vaccine protection against high levels of viral replication during only the first weeks following an AIDS virus infection may provide sufficient protection against central memory CD4+ T cell loss to confer a survival advantage to infected individuals. Moreover, current models of large human HIV-1 vaccine efficacy trials propose the use of set point viral load and total CD4+ T lymphocyte count as surrogate markers for a beneficial vaccine effect (21, 22). It has been presumed that a lower set point viral load or a higher set point CD4+ T lymphocyte count after infection will portend a better AIDS free survival. The results of the present study indicate that set point viral load and total CD4+ T lymphocyte count may not have predictive value in this setting. Rather, the quantitation of central memory CD4+ T cells in a vaccine trial several months following infection may be an important immune correlate of long term protection and predict the efficacy of an HIV-1 vaccine.